Thyroid hormone is necessary for the development of the nervous system. A lack of thyroid hormone in early development in the mammalian fetus or neonate can result in mental retardation and other neurological defects, including deafness. Hearing is one of the most sensitive functions that is under the control of thyroid hormone. However, despite the importance of thyroid hormone for hearing, its actions in promoting the development of the auditory system are incompletely understood. The goals of the project are to elucidate the functions of thyroid hormone in the auditory system and to identify the genes that mediate these functions. Progress: 1. Study of mammalian models with mutation in the Thra and Thrb thyroid hormone receptor genes has revealed deafness phenotypes with a range of cellular defects in the cochlea in the inner ear. We continue to investigate individual and combined mutations in the Thra and Thrb genes in mouse models to determine the genetic basis for thyroid hormone actions on the auditory system. The studies suggest both independent and shared functions for the Thra and Thrb genes in the development of hearing. 2. Our data show that genes encoding deiodinases, thyroid hormone-metabolizing enzymes, are important for hearing. The results suggest that changing patterns of expression of the deiodinase genes encoding both activating and inactivating enzymes (Dio2 and Dio3, respectively) cause deafness in mouse genetic models. The findings suggest that these enzymes are important within target tissues for modifying precisely where and when thyroid hormone acts in the auditory system. Thus, the action of thyroid hormone upon the auditory system incorporates both an endocrine and a paracrine component involving local control by deiodinases. In addition, recent study has identified specific expression patterns of transporter genes for thyroid hormone uptake by target tissues. These findings suggest novel pathways of thyroid hormone action, including in the uptake and transfer of ligand in the complex structures of the auditory system. 3. We continue to investigate the target genes that reside downstream of thyroid hormone receptor isoforms in the tissues of the immature auditory system. We are performing screens to identify cochlear genes that may be abnormally expressed in deaf mice defective for thyroid hormone signaling. Further studies are investigating the expression and function of several candidate target genes in the auditory system.